1. Nalley, Catlin

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Seventy-four percent of patients with pancreatic cancer die within 1 year of diagnosis and 91 percent will succumb to their disease within 5 years. A lack of early detection and a need for more effective treatment approaches both factor into the low survival rates among these patients.

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"The majority of patients with pancreatic cancer present with advanced or metastatic disease," noted Aatur Singhi, MD, PhD, Assistant Professor of Pathology at the University of Pittsburgh. "So, how do we treat these patients?"


To improve survival rates and address these challenges, researchers sought to create a more personalized approach by utilizing genetic signatures to better match drugs to patients (Gastroenterology 2019; doi:10.1053/j.gastro.2019.02.037).


"We have seen a paradigm shift in other cancers, such as breast and lung, where we utilize genomic information to direct targeted therapies," said senior author Nathan Bahary, MD, PhD, Associate Professor of Medicine at the University of Pittsburgh and Clinical Oncologist at UPMC Hillman Cancer Center. "However, to date, this hasn't really been the case for pancreatic cancer.


"Patients who have specific molecular alterations and are able to get directed treatments up front rather than in later lines of therapy often have a survival advantage," he continued. "It behooves us to bring pancreatic cancer into the 21st century as well, and that paper offers a guide on how it can be done."


Study Details

Researchers performed targeted genomic profile analyses of 3,594 pancreatic ductal adenocarcinomas (PDAC) samples from an international cohort.


"We did a comprehensive, targeted sequencing analysis of genomic alterations that are known to occur in all types of cancers," explained Singhi, lead author of the study. "We are focused on a targeted approach because we want to increase the sensitivity. Looking for alterations that truly have a corresponding drug analog that is utilized in therapy [is important]. These are much more valuable than looking at an obscure gene we know nothing about."


The researchers also evaluated for gene fusions. "We isolated RNA and identified specific gene fusions that can occur in certain cancers that we know can be targeted in pancreatic cancer as well," Singhi said.


Tumor mutation burden (TMB) and microsatellite instability (MSI) status also were assessed. "It is known that patients with MSI in their cancer as well as those with a high TMB are potentially susceptible to immunotherapy," Singhi explained.


Key Findings

Researchers found that 17 percent of pancreatic cancers have genomic alterations that could be targeted by existing chemotherapies.


Data showed that the most frequently altered genes in PDAC tissues included KRAS, TP53, CDKN2A, and SMAD4. KRAS mutations were detected in 88 percent of samples.


Among PDACs without KRAS mutations, researchers "found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets; n=132; 4%), as well as gene fusions (n=51), gene amplifications (n=35), genes with missense mutations (n=30), and genes that contain deletions (n=16)."


Among PDAC samples evaluated for MSI (n=2,563) and TMB (n=1,021), MSI-H and/or TMB-H phenotypes were detected in 0.5 percent of samples, according to study authors.


Researchers also found evidence of heritable genes, including some in the BRCA family associated with breast cancer, which can predispose whole families to pancreatic cancer. "Understanding the hereditary aspects of pancreatic cancer is extremely important," Singhi noted. "We found a significant number of patients had germline alterations in the DNA repair genes, the same genes that are associated with breast cancer, ovarian cancer, and other neoplasms."


Additionally, the newly discovered biomarkers from this study can be added to the PancreaSeq platform, a clinical molecular test previously developed by Singhi and colleagues. This platform evaluates common pancreatic cysts and identifies which cases may lead to cancer.


Overall, this study highlights potential treatment approaches for patients as well as new directions for pancreatic cancer research. "These findings shed light on certain avenues and pathways for future study," noted Bahary. "For instance, a lot of these genes fall in the category of DNA damage response and may have common pathways of treatment or may give you common pathways to leverage immune therapy, which until now has not worked particularly well for pancreatic cancer."


Ongoing Research

This study lays the foundation for continued investigation of pancreatic cancer and the authors plan to continue sequencing additional patients.


"We have sequenced more than 4,000 to date and are still going through the data," noted Singhi. "We are also inputting identified biomarkers into early detection assays, like PancreaSeq, in an effort to improve the way we evaluate patients as well as early detection of the disease."


Study authors also plan to take a closer look at other pancreatic neoplasms beyond PDAC. The next area of study will involve the comprehensive genome of pancreatic neuroendocrine tumors-the second most common pancreatic cancer, according to Singhi.


"Every pancreatic cancer is different, and performing molecular profiling of each patient's tumor could help determine the best treatment options," he noted, in a statement.


"Rather than blindly giving patients the same chemotherapy, we want to tailor a patient's chemo to their tumor type," Singhi concluded. "A one-size-fits-all approach isn't going to work. Therefore, we would like to make molecular profiling standard of care for patients with pancreatic cancer."


Catlin Nalley is associate editor.